REVIEWPathogenesis, classification, and therapy of eosinophilia and eosinophil disorders
Section snippets
Biology of eosinophils and reactive eosinophilia
Eosinophils are myelopoietic effector cells that produce and store a number of biologically active molecules, including eosinophil cationic protein (ECP), major basic protein (MBP), eosinophil neurotoxin, lipid mediators (prostaglandins, leukotriens, and thromboxan A2), and cytokines such as tumor necrosis factor (TNF) alpha.[1], [2], [3] Once activated, eosinophils release their mediators and cytokines, thereby influencing homeostasis and tissue integrity.3 In case of massive and permanent
Diagnostic algorithm and initial investigations
Several different pathologic conditions may lead to an increased production and/or accumulation of reactive/non-neoplastic eosinophils. In most instances, an underlying cause is known or is revealed after initial investigations. Such investigations include a detailed case history, thorough physical examination, X-ray of chest (and lung function test if necessary), electrocardiogram and echocardiogram, ultrasound of abdomen, a complete blood count with microscopic differential count, and a
The hypereosinophilic syndrome (HES)
Major diagnostic criteria for the so called hypereosinophilic syndrome are (i) a permanent eosinophil count of >1500/μL (for at least 6 months) and (ii) the typical end organ damage.[29], [30], [31], [32], [33], [34] In addition, unrelated disorders and transient eosinophilia have to be excluded. Patients with HES may suffer from multiorgan involvement or from isolated end organ damage. In many cases, lung- or endomyocardial fibrosis is seen. In other patients, thrombosis, neurologic symptoms,
Diagnostic approach in patients with suspected hematologic neoplasm
In patients in whom eosinophilia is unlikely to be reactive and/or is accompanied by other blood count abnormalities or by typical end organ damage (HES), specific blood tests are performed, and the bone marrow is examined. Fig. 2 provides a diagnostic algorithm for these patients. Most molecular studies can be performed using peripheral blood and thus yield rapid diagnostic results.[25], [34], [35] Depending on clinical and blood findings, initial tests include markers indicative of (a) a stem
Chronic eosinophilic leukemia (CEL)
Chronic eosinophilic leukemia (CEL) is a myeloproliferative neoplasm defined by the following criteria: persistent eosinophilia (>1500/μL for at least 6 months) and molecular or/and cytogenetic evidence of monoclonal eosinophils, and/or presence of blast cells in the peripheral blood (>2%) or bone marrow (5–19%), and exclusion of all other hematologic and non-hematologic causes of eosinophilia, with recognition of the principle possibility of coexistence of two separate disorders (e.g.
Myeloproliferative and stem cell neoplasms, myelodysplastic syndromes (MDS), and overlap syndromes
Eosinophilia is typically found in various myeloproliferative neoplasms (MPN). In Philadelphia chromosome positive (Ph+) CML, eosinophilia and basophilia are almost always present at diagnosis, and often also when the disease progresses. In patients with typical JAK2 V617F+ MPN, eosinophilia is less frequently detected, but may also occur.25 However, in distinct variants of (atypical) MPN, namely those that develop on the basis of (in association with) an oncogenic form of PDGFRA, PDGFRB, or
Mast cell disorders – systemic mastocytosis (SM) and mast cell leukemia
Although indolent and aggressive variants of SM may be accompanied by eosinophilia (SM-eo), an increase in eosinophils is more frequently observed in advanced forms of the disease, i.e. smouldering SM (SSM-eo), aggressive SM (ASM-eo), and mast cell leukemia (MCL-eo).[51], [52] Moreover, eosinophilia in SM is of prognostic significance.52 A subvariant of ASM-eo is lymphadenopathic SM with eosinophilia.[36], [53] In advanced SM and some patients with ISM, eosinophils are considered to belong to
Malignant lymphomas and other lymphoid neoplasms
A number of lymphoid neoplasms may be accompanied by eosinophilia. Such neoplasms include T cell lymphomas, Hodgkin’s disease, and less frequently B cell Non Hodgkin’s lymphomas (NHL), NK cell neoplasms, acute lymphoblastic leukemia (ALL), and other B cell malignancies.[25], [33], [38], [39] In an early phase of disease, eosinophilia may be the only sign for a (T cell) lymphoma. In other patients, a monoclonal T cell population (clone) is detected by PCR or immunophenotyping, but does not
The WHO classification of eosinophil disorders
The WHO classification 2008 defines two groups of patients with neoplastic eosinophils.[60], [61] One group of patients is suffering from a “myeloid or lymphoid (or stem cell) neoplasm with eosinophilia and abnormalities in PDGFRA, PDGFRB, or FGFR1 genes”.60 The second group, integrated in a subchapter as MPN category, is termed “chronic eosinophilic leukemia, not otherwise specified”.61 The advantage of the WHO classification is that it is based on potential targets, and therefore is in
Therapy of patients with hypereosinophilic disorders
A number of molecular targets related to CEL or to other hematopoietic malignancies presenting with eosinophilia have been defined recently.[25], [38], [39], [40], [41], [42], [43], [44], [62] A summary of potential targets is shown in Table 3. In the individual patient, it is of importance to define the nature of eosinophilia by application of such markers, but also to define the clinical impact of eosinophilia by appropriate staging and assessment of organ infiltration and organ damage, i.e.
Summary and future perspectives
Eosinophilia is an important diagnostic and/or prognostic feature in various myeloid neoplasms. We recommend the use of the appendix ‘eo’ (e.g. MPN-eo, SM-eo) for patients in whom this important diagnostic checkpoint has been reached. Cytogenetic and molecular markers are then applied, and are helpful for determining the final diagnosis. In addition, several of these markers also represent important therapeutic targets. Patients with oncogenic variants of the PDGFR are candidates for treatment
Conflict of interest statement
The author has no conflict of interest.
References (74)
Eosinophils: structure and functions
Curr Opin Immunol
(1994)Mechanisms of eosinophil-associated inflammation
J Allergy Clin Immunol
(2000)- et al.
Mechanisms of eosinophilia in the pathogenesis of hypereosinophilic disorders
Immunol Allergy Clin N Am
(2007) - et al.
Cardiovascular manifestations of hypereosinophilic syndromes
Immunol Allergy Clin N Am
(2007) - et al.
Identification of pure and mixed basophil colonies in culture of human peripheral blood and marrow cells
Blood
(1984) - et al.
Heterogeneity of human peripheral blood eosinophil-type colonies: evidence for a common basophil–eosinophil progenitor
Blood
(1985) - et al.
Lymphoid and myeloid differentiation of single human CD34+, HLA-DR+, CD38− hematopoietic stem cells
Blood
(1994) - et al.
Early commitment to the eosinophil lineage by cultured human peripheral blood CD34+ cells: messenger RNA analysis
J Allergy Clin Immunol
(1996) - et al.
Interleukin-3 is a differentiation factor for human basophils
Blood
(1989) - et al.
Interleukin-5, interleukin-3, and granulocyte–macrophage colony-stimulating factor cross-compete for binding to cell surface receptors on human eosinophils
J Biol Chem
(1991)
GM-CSF, IL-3 and IL-5: cross-competition on human haemopoietic cells
Immunol Today
Eosinophilia: a study of 100 hospitalized patients
Eur J Intern Med
Evaluation and differential diagnosis of marked, persistent eosinophilia
Immunol Allergy Clin N Am
Eosinophilic disorders
J Allergy Clin Immunol
The hypereosinophilic syndromes working group. Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report
J Allergy Clin Immunol
Eosinophilic disorders: molecular pathogenesis, new classification, and modern therapy
Best Pract Res Clin Haematol
Diagnostic criteria and classification of mastocytosis: a consensus proposal
Leuk Res
Chronic eosinophilic leukemias and the myeloproliferative variant of the hypereosinophilic syndrome
Immunol Allergy Clin N Am
CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy
Blood
Imatinib therapy for hypereosinophilic syndrome and other eosinophilic disorders
Blood
The FIP1L1-PDGFRA fusion gene cooperates with IL-5 to induce murine hypereosinophilic syndrome (HES)/chronic eosinophilic leukemia (CEL)-like disease
Blood
Prevalence and clinical characteristics of myelodysplastic syndrome with bone marrow eosinophilia or basophilia
Blood
A case of smouldering mastocytosis with peripheral blood eosinophilia and lymphadenopathy
Leuk Res
Eosinophilia in systemic mastocytosis: clinical and molecular correlates and prognostic significance
J Allergy Clin Immunol
Multilineage hematopoietic involvement in systemic mastocytosis
Leuk Res
Eosinophils are derived from the neoplastic clone in patients with systemic mastocytosis and eosinophilia
Leuk Res
Blood eosinophilia: a new paradigm in disease classification, diagnosis, and treatment
Mayo Clin Proc
The small molecule tyrosine kinase inhibitor AMN107 inhibits TEL-PDGFRbeta and FIP1L1-PDGFRalpha in vitro and in vivo
Blood
Dasatinib inhibits the growth and survival of neoplastic human eosinophils (EOL-1) through targeting of FIP1L1-PDGFRα
Exp Hematol
PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFRalpha-induced myeloproliferative disease
Cancer Cell
Sorafenib is a potent inhibitor of FIP1L1-PDGFRalpha and the imatinib-resistant FIP1L1-PDGFRalpha T674I mutant
Blood
The FIP1L1-PDGFRA T674I mutation can be inhibited by the tyrosine kinase inhibitor AMN107 (nilotinib)
Blood
Low-dose imatinib mesylate leads to rapid induction of major molecular responses and achievement of complete molecular remission in FIP1L1-PDGFRA-positive chronic eosinophilic leukemia
Blood
The biology of the eosinophilic leukocyte
Annu Rev Med
Eosinophils: biological properties and role in health and disease
Clin Exp Allergy
Hemopoietic progenitors and cytokines in allergic inflammation
Allergy
Circulating eosinophil/basophil progenitors and nasal mucosal cytokines in seasonal allergic rhinitis
Allergy
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